Alzheimer's disease (AD) is a debilitating mental disorder involving severe cognitive impairment. Over 10 million people are afflicted with AD, resulting in healthcare costs of $350 billion. A drug that could delay the onset and development of AD has been estimated to be worth over $50 billion. However, there is presently no effective treatment for AD. The neuropathological mechanisms of AD involves production of the neurotoxic beta-peptide (betaP) by proteolytic processing of the amyloid precursor protein (APP). The betaP becomes deposited in amyloid plaques of AD brains and mediates neuronal cell death, indicating the betaP to be a key factor in the development of AD. Multiple forms of betaP are produced by proteases known as 'gamma-secretases' that convert the amyloid precursor protein (APP) into the smaller, neurotoxic betaP. It is believed that inhibitors of gamma-secretases will block betaP production and delay the progression of neurodegeneration in AD. However, such inhibitors have not been discovered because the authentic gamma-secretases have been unknown. ActiveSite Biotech has identified the authentic gamma-secretases that produce betaP. We propose to use our proprietary technology to develop and optimize highly sensitive gamma-secretase assays in this Phase I study that will allow screening of inhibitors of gammaP production. Phase I will assess the feasibility of gamma-secretase activity assays to monitor inhibition by commercially available protease inhibitors; this Phase I study will also determine whether distinct y-secretases can be separated for more selective drug screening. Results from Phase I will be used as the basis for future Phase II investigations to screen small molecule combinatorial libraries for inhibitors of gamma-secretase activity and betaP production. These identified compounds will be developed by ActiveSite Biotech as drugs for the therapeutic treatment of Alzheimer's disease. PROPOSED COMMERCIAL APPLICATIONS: The gamma-secretase assays developed in this project are the subject of a patent application owned by Professor Vivian Hook, which she is licensing to Activesite Biotech. Upon issuance of this patent, Activesite Biotech will be in a position to exclusively sell, license, and partner the gamma-secretase assays. Activesite Biotech will use the assay to identify and develop novel, effective treatments for Alzheimer's disease (AD). The estimated market value for an effective treatment of AD is estimated to be $50 billion.